Relaxin and phosphodiesterases collaborate during decidualization

During the evolution of mammals, the endometrium has developed for one reason only: to implant an embryo in the uterus. In higher primates, should an oocyte fail to be fertilized, then the endometrial layer is sloughed off during menses and the menstrual cycle starts again with a new round of endometrial differentiation. This stromal differentiation process is called decidualization and is accompanied in vivo by sustained high levels of intracellular cAMP. The present study was conducted to determine whether manipulation of cAMP-phosphodiesterase (PDE) activities in cultured human endometrial stromal cells could positively influence the decidualization process. The combination of relaxin treatment with inhibition of PDE4 by the specific inhibitor rolipram induced a strong increase in relaxin-mediated cAMP production, both acutely, after 20 min, and after long-term treatment for 3 days, to promote a sustained intracellular cAMP concentration. Moreover, there was a dramatic synergistic effect on the decidualization phenotype, characterized both morphologically and by increased production of prolactin and insulin-like growth factor binding protein-1 gene transcripts. The observations that expression of PDE4D transcripts were selectively increased by cAMP and that inhibition of protein kinase A by H89 to potentially block negative feedback regulation enhanced the relaxin/rolipram-mediated cAMP accumulation lead to a complex picture of cAMP regulation in these cells. There appears to be a coordinated contribution by relaxin and PDE4 at different levels to promote a sustained increased cAMP concentration during decidualization, and thus to provide an adequate maternal interface for the implanting blastocyst.